Are we missing ‘previously treated’ smear-positive pulmonary tuberculosis under programme settings in India? A cross-sectional study

Study design and participants

This was a cross-sectional study involving new smear-positive pulmonary TB patients (≥ 15 y) from marginalised and vulnerable populations that were registered for treatment under the RNTCP in India between March 2016 and February 2017.

Setting

National TB programme (2016–17): India’s RNTCP infrastructure included national, state, district and sub-district level administrative units (one for 250 000 to 500 000 population) and designated microscopy centres for sputum smear microscopy⁸. Before starting TB treatment, the medical officer in the health facility classified the patients as ‘new’ or ‘previously treated’.

During the study period (March 2016 to February 2017), new patients received two months of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol followed by four months of Isoniazid, Rifampicin and Ethambutol. ‘Previously treated’ patients received two months of Isoniazid, Rifampicin, Pyrazinamide, Ethambutol and Streptomycin, one month of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol and five months of Isoniazid, Rifampicin and Ethambutol. Among TB patients, a subset of patients who were at high risk to have MDR-TB (presumptive MDR-TB patients) underwent genotypic drug susceptibility testing (DST). These included patients previously treated for TB, patients with a TB-HIV co-infection, patients who upon follow up during TB treatment were smear-positive and contacts of a confirmed MDR-TB patient.

Project Axshya: Project Axshya is implemented in India by the South-East Asia office of the International Union against Tuberculosis and Lung Disease (The Union) to enhance the reach and visibility of RNTCP services among marginalised and vulnerable populations and to mitigate the impact of TB on the country (see Box for criteria for marginalised and vulnerable populations). Axshya SAMVAD (SAMVAD is an acronym for sensitization and advocacy in marginalised and vulnerable areas of the district) is the ACF strategy under the project. The word ‘SAMVAD’ in Sanskrit language means ‘conversation’. In 2016–17, the project covered 285 districts spread across 19 states.

Axshya SAMVAD study: This study was conducted among new smear-positive pulmonary TB patients to determine the effectiveness of Axshya SAMVAD on diagnosis and treatment initiation delays, costs due to TB diagnosis and treatment outcomes^6,7. We included all new smear-positive pulmonary TB patients from marginalised and vulnerable populations that were detected through ACF and registered under the programme in the 18 randomly sampled Axshya districts (simple random sampling) during March 2016 to February 2017. Every month in the same districts, we randomly sampled an equal number of new smear-positive pulmonary TB patients registered through PCF from marginalised and vulnerable populations (simple random sampling)^6,7. Random numbers for simple random sampling were generated using Microsoft Excel.

Data collection

Under Axshya SAMVAD study, we collected data for each study participant through record review (age, sex, ACF/PCF status, residence (urban/rural), distance of residence from microscopy centre, sputum smear grade, weight, diabetes status and HIV status) and patient interviews at their residence. Patient interviews were set up during the review of the participant’s record. Before starting the patient interviews, we enquired about their past history of TB treatment for at least one month either from the public or private sector. Those with a past history of treatment were excluded from the Axshya SAMVAD study and referred to the programme for appropriate management. These constitute ‘misclassification’ for the purpose of present analysis.

Data analysis

We double entered and validated the data using EpiData Entry software⁹ (version 3.1, EpiData Association, Odense Denmark). We analysed the data using STATA (version 12.1, copyright 1985–2011 StataCorp LP USA)¹⁰. We used frequency and proportions (0.95 confidence intervals (CI)) to summarise (infer) the extent of misclassification. Adjusted analysis was done using log binomial regression to determine the factors associated with misclassification. Variables collected during record review (age, sex, ACF/PCF status, residence (urban/rural), distance of residence from microscopy centre and sputum smear grade) were included in the adjusted analysis. Baseline weight was missing in two-fifths of patients; baseline diabetes status was missing for more than three-fifths and HIV status was missing for two-fifths. Hence, we excluded them from the adjusted analysis. The association was summarized (inferred) using adjusted prevalence ratios (95% CIs).

Ethics

The Axshya SAMVAD study was approved by the Ethics Advisory Group of The Union, Paris, France (EAG number 15/15, dated 28 September 2015). We conducted the study after receiving approvals from the State Tuberculosis Officers in the respective states (18 randomly sampled Axshya districts belonged to seven states). We obtained written informed consent for participation from all the study participants.

Key findings

About one in ten ‘new’ TB patients had a past history of TB treatment. This misclassification meant that these patients received the wrong treatment regimen as per the national guidelines at the time. This is similar to the RNTCP report of 2018³ and previous documentation in 2007⁵. The misclassification among new smear-positive TB patients was two times higher than the 4.5% reported from Malawi in 2000¹¹.

One possible reason for this might be a lack of attention on the part of the medical officer to enquire for previous history of TB before starting treatment. Ambiguity in classification when there was a large gap between previous and current treatment, absence of treatment records and patients’ reluctance to disclose previous treatment details due to possible stigma (fear of being seen as a ‘problem patient’) could be the other reasons⁵.

Limitations

This study has some limitations. First, this programmatically relevant finding was incidental and part of a larger study (Axshya SAMVAD study) and hence, we did not systematically record the details of past TB treatment (when, duration of treatment, whether under programme or in private sector) and the reasons for misclassification. Secondly, as patients with misclassification were excluded from the Axshya SAMVAD study, we do not know what happened to them, including their treatment outcomes. Thirdly, we did not include smear-negative pulmonary TB and extrapulmonary TB patients as they were not part of the Axshya SAMVAD study. In Malawi (2000)¹¹, they had a higher risk of misclassification when compared to smear-positive pulmonary TB patients. Finally, non-response was a limitation. However, in a best-case scenario (assuming all 108 non-responders did not have previous history of TB treatment), the proportion of misclassification would have been 8.9% (56/629) which is still programmatically significant.

Implications for the TB programme

Limitations notwithstanding, our study has programme implications. Of the new smear-positive pulmonary TB patients registered in India in 2016, 21% had an unfavourable outcome³. Some of these unfavourable outcomes can be explained by wrong management – patients getting an inferior treatment regimen (previously treated patients being treated with a regimen meant for new cases) and missing an opportunity for drug susceptibility testing (as previously treated patients were eligible for DST at the time). Inferior regimen might have also contributed to amplification of resistance in those who may have primary or acquired drug resistance (from prior treatment) and MDR-TB. This has been happening for over 10 years so one can see why India now faces the serious problem of drug resistant TB.

India has recently adopted the World Health Organization (WHO) recommendation that the category II regimen (for ‘previously treated’ patients) ‘should no longer be prescribed and drug susceptibility testing should be conducted to inform the choice of treatment regimen’¹². To make this a reality, India now recommends universal DST, meaning all diagnosed TB patients are eligible for testing via the Xpert MTB/RIF assay^® (Cepheid Sunnyvale USA) followed by first-line (if rifampicin susceptible) or second-line line probe assay (if rifampicin resistant)^4,13. This further means that both new and previously treated patients are treated with the same regimen^4,8,14. Hence, in the present scenario, the impact of misclassification on individual patient management is minimal. This was not the case at the time of conduct of this study. Despite these developments, we think asking for previous treatment history is still relevant for two reasons. First, the information on the proportion of previously treated patients is epidemiologically an important piece of information and is regularly reported to the WHO for monitoring the global TB epidemic. Second, the universal DST is not a reality in every part of the country and in such instances, prioritizing previously treated patients for DST is a better strategy, given the higher prevalence of drug-resistant TB among them.

Recommendations

Our findings were based on patients from marginalised and vulnerable populations and this limits our generalisability to TB patients registered from the general population. The programme should consider replicating similar studies among patients from the general population with a possible sub-group to look for rural-urban differences.

Since 2017, the revised laboratory register at the level of designated microscopy centres under the RNTCP (one per 50 000 to 100 000 population) also captures this information of previous treatment⁸. RNTCP staff needs to be re-sensitized to “ask” for previous history of TB treatment. Hence, complete filling of the revised laboratory register at microscopy centres should be closely monitored by the programme and future operational research should focus on this.

Systematic qualitative enquiry is recommended to understand the ‘why’ (why does it happen) and ‘how’ (how can it be addressed) of misclassification. In the national case-based TB notification software (NIKSHAY), record linkage and deduplication using key attributes may be considered to identify repeat notification of the same person separated by a time period.

Underlying data

figshare: Underlying data. https://dx.doi.org/10.6084/m9.figshare.7756688¹⁵

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Extended data

figshare: Questionnaire Axshya SAMVAD study. https://dx.doi.org/10.6084/m9.figshare.7768589¹⁶

This project contains the following extended data:

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).